Oxidation process using tempo

ABSTRACT

The present invention relates to an oxidation using sodium chlorite in the presence of a catalytic amount of TEMPO and sodium hypochlorite which converts the penultimate intermediate bearing a primary alcohol to the target endothelin antagonist compound of Formula I having a carboxylic acid ##STR1##

This application claims priority from Provisional Application Ser. No.60/081,196 filed Apr. 9, 1998.

BACKGROUND OF THE INVENTION

The present invention relates to an oxidation using sodium chlorite inthe presence of a catalytic amount of TEMPO and sodium hypochloritewhich converts the penultimate intermediate bearing a primary alcohol tothe target endothelin antagonist compound having a carboxylic acid. Thisoxidation method avoids the disposal issues associated with running aJones oxidation reaction, as well as reducing the epimerization of anyα-chiral centers and is a one step procedure. For substrates prone tochlorination with the TEMPO-NaClO protocol, the instant inventionreduces this problem.

The compound possessing a high affinity for at least one of two receptorsubtypes, are responsible for the dilation of smooth muscle, such asblood vessels or in the trachea. The endothelin antagonist compoundsprovide a potentially new therapeutic target, particularly for thetreatment of hypertension, pulmonary hypertension, Raynaud's disease,acute renal failure, myocardial infarction, angina pectoris, cerebralinfarction, cerebral vasospasm, arteriosclerosis, asthma, gastric ulcer,diabetes, restenosis, prostatauxe endotoxin shock, endotoxin-inducedmultiple organ failure or disseminated intravascular coagulation, and/orcyclosporin-induced renal failure or hypertension.

Endothelin is a polypeptide composed of amino acids, and it is producedby vascular endothelial cells of human or pig. Endothelin has a potentvasoconstrictor effect and a sustained and potent pressor action(Nature, 332, 411-415 (1988)).

Three endothelin isopeptides (endothelin-1, endothelin-2 andendothelin-3), which resemble one another in structure, exist in thebodies of animals including human, and these peptides havevasoconstriction and pressor effects (Proc. Natl. Acad, Sci, USA, 86,2863-2867 (1989)).

As reported, the endothelin levels are clearly elevated in the blood ofpatients with essential hypertension, acute myocardial infarction,pulmonary hypertension, Raynaud's disease, diabetes or atherosclerosis,or in the washing fluids of the respiratory tract or the blood ofpatients with asthmaticus as compared with normal levels (Japan, J.Hypertension, 12, 79, (1989), J. Vascular medicine Biology, 2, 207(1990), Diabetologia, 33, 306-310 (1990), J. Am. Med. Association, 264,2868 (1990), and The Lancet, ii, 747-748 (1989) and ii, 1144-1147(1990)).

Further, an increased sensitivity of the cerebral blood vessel toendothelin in an experimental model of cerebral vasospasm (Japan. Soc.Cereb. Blood Flow & Metabol., 1, 73 (1989)), an improved renal functionby the endothelin antibody in an acute renal failure model (J. Clin,invest., 83, 1762-1767 (1989), and inhibition of gastric ulcerdevelopment with an endothelin antibody in a gastric ulcer model(Extract of Japanese Society of Experimental Gastric Ulcer, 50 (1991))have been reported. Therefore, endothelin is assumed to be one of themediators causing acute renal failure or cerebral vasospasm followingsubarachnoid hemorrhage.

Further, endothelin is secreted not only by endothelial cells but alsoby tracheal epithelial cells or by kidney cells (FEBS Letters, 255,129-132 (1989), and FEBS Letters, 249, 42-46 (1989)).

Endothelin was also found to control the release of physiologicallyactive endogenous substances such as renin, atrial natriuretic peptide,endothelium-derived relaxing factor (EDRF), thromboxane A₂,prostacyclin, noradrenaline, angiotensin II and substance P (Biochem.Biophys, Res. Commun., 157, 1164-1168 (1988); Biochem. Biophys, Res.Commun., 155, 20 167-172 (1989); Proc. Natl. Acad. Sci. USA, 85 19797-9800 (1989); J. Cardiovasc. Pharmacol., 13, S89-S92 (1989); Japan.J. Hypertension, 12, 76 (1989) and Neuroscience Letters, 102, 179-184(1989)). Further, endothelin causes contraction of the smooth muscle ofgastrointestinal tract and the uterine smooth muscle (FEBS Letters, 247,337-340 (1989); Eur. J. Pharmacol., 154, 227-228 (1988); and Biochem.Biophys Res. Commun., 159,317-323 (1989)). Further, endothelin was foundto promote proliferation of rat vascular smooth muscle cells, suggestinga possible relevance to the arterial hypertrophy (Atherosclerosis, 78,225-228 (1989)). Furthermore, since the endothelin receptors are presentin a high density not only in the peripheral tissues but also in thecentral nervous system, and the cerebral administration of endothelininduces a behavioral change in animals, endothelin is likely to play animportant role for controlling nervous functions (Neuroscience Letters,97, 276-279 (1989)). Particularly, endothelin is suggested to be one ofmediators for pain (Life Sciences, 49, PL61-PL65 (1991)).

Internal hyperplastic response was induced by rat carotid artery balloonendothelial denudation. Endothelin causes a significant worsening of theinternal hyperplasia (J. Cardiovasc. Pharmacol., 22, 355-359 &371-373(1993)). These data support a role of endothelin in thephathogenesis of vascular restenosis. Recently, it has been reportedthat both ET_(A) and ET_(B) receptors exist in the human prostate andendothelin produces a potent contraction of it. These results suggestthe possibility that endothelin is involved in the pathophysiology ofbenign prostatic hyperplasia (J. Urology, 151, 763-766(1994), MolecularPharmocol., 45, 306-311(1994)).

On the other hand, endotoxin is one of potential candidates to promotethe release of endothelin. Remarkable elevation of the endothelin levelsin the blood or in the culture supernatant of endothelial cells wasobserved when endotoxin was exogenously administered to animals or addedto the culture endothelial cells, respectively. These findings suggestthat endothelin is an important mediator for endotoxin-induced diseases(Biochem. Biophys. Commun., 161,1220-1227 (1989); and Acta Physiol.Scand., 137, 317-318 (1989)).

Further, it was reported that cyclosporin remarkably increasedendothelin secretion in the renal cell culture (LLC-PKL cells) (Eur. J.Pharmacol., 180, 191-192 (1990)). Further, dosing of cyclosporin to ratsreduced the glomerular filtration rate and increased the blood pressurein association with a remarkable increase in the circulating endothelinlevel. This cyclosporin-inducea renal failure can be suppressed by theadministration of endothelin antibody (Kidney Int., 37, 1487-1491(1990)). Thus, it is assumed that endothelin is significantly involvedin the pathogenesis of the cyclosporin-induced diseases.

Such various effects of endothelin are caused by the binding ofendothelin to endothelin receptors widely distributed in many tissues(Am. J. Physiol., 256, R856-R866 (1989)).

It is known that vasoconstriction by the endothelins is caused via atleast two subtypes of endothelin receptors (J. Cardiovasc. Pharmacol.,17(Suppl.7), S119-SI21 (1991)). One of the endothelin receptors isET_(A) receptor Selective to ET-1 rather than ET-3, and the other isET_(B) receptor equally active to ET-1 and ET-3. These receptor proteinsare reported to be different from each other (Nature, 348, 730-735(1990)).

These two subtypes of endothelin receptors are differently distributedin tissues. It is known that the ET_(A) receptor is present mainly incardiovascular tissues, whereas the ET_(B) receptor is widelydistributed in various tissues such as brain, kidney, lung, heart andvascular tissues.

Substances which specifically inhibit the binding of endothelin to theendothelin receptors are believed to antagonize various pharmacologicalactivities of endothelin and to be useful as a drug in a wide field.Since the action of the endothelins is caused via not only the ET_(A)receptor but also the ET_(B) receptor, novel non-peptidic substanceswith ET receptor antagonistic activity to either receptor subtype aredesired to block activities of the endothelins effectively in variousdiseases.

Endothelin is an endogenous substance which directly or indirectly (bycontrolling liberation of various endogenous substances) inducessustained contraction or relaxation of vascular or non-vascular smoothmuscles, and its excess production or excess secretion is believed to beone of pathogeneses for hypertension, pulmonary hypertension, Raynaud'sdisease, bronchial asthma, gastric ulcer, diabetes, arteriosclerosis,restenosis, acute renal failure, myocardial infarction, angina pectoris,cerebral vasospasm and cerebral infarction. Further, it is suggestedthat endothelin serves as an important mediator involved in diseasessuch as restenosis, prostatauxe, endotoxin shock, endotoxin-inducedmultiple organ failure or disseminated intravascular coagulation, andcyclosporin-induced renal failure or hypertension.

Two endothelin receptors ET_(A) and ET_(B) are known so far andantagonists of these receptors have been shown to be potential drugtargets. EP 0526708 Al and WO 93/08799 Al are representative examples ofpatent applications disclosing non-peptidic compounds with allegedactivity as endothelin receptor antagonists.

The present invention discloses a process for preparing a compound ofFormula I: ##STR2## comprising the following steps: 1) adding to acompound of Formula II in a solvent, ##STR3## a solution of phosphatebuffer to maintain a pH of about 4.0 to about 8.0;

2) maintaining the phosphate-buffered biphasic mixture of the compoundof Formula II at about 0° C. to about 50° C.;

3) adding sodium chlorite and a catalytic amount of TEMPO to themixture; and

4) charging the mixture with a catalytic amount of sodium hypochloriteto oxidize to the compound of Formula I.

SUMMARY OF THE INVENTION

The present invention discloses a process for preparing a compound ofFormula I: ##STR4## wherein: ##STR5## represents: a) 5- or 6-memberedheterocyclyl containing one, two or three double bonds, but at least ondouble bond and 1, 2 or 3 heteroatoms selected from O, N and S, theheterocyclyl is unsubstituted or substituted with one, two or threesubstituents selected from the group consisting of: OH, CO₂ R⁴, Br, Cl,F, I, CF₃, C₁ -C₈ alkoxy, C₁ -C₈ alkyl, C₂ -C₈ alkynyl, C₃ -C₈cycloalkyl, and CO(CH₂)_(n) CH₃ ;

b) 5- or 6-membered carbocyclyl containing one or two double bonds, butat least one double bond, the carbocyclyl is unsubstituted orsubstituted with one, two or three substituents selected from the groupconsisting of: OH, CO₂ R⁴, Br, Cl, F, I, CF₃, C₁ -C₈ alkoxy, C₁ -C₈alkyl, C₂ -C₈ alkynyl, C₃ -C₈ cycloalkyl, and CO(CH₂)_(n) CH₃ ;

c) aryl, wherein aryl is as defined below,

C₁ -C₈ alkoxy, C₁ -C₈ alkyl, C₂ -C₈ alkynyl, C₃ -C₈ cycloalkyl, areunsubstituted or substituted with one, two or three substituentsselected from the group consisting of: OH, CO₂ R⁴, Br, Cl, F, I, CF₃, C₁-C₈ alkoxy, C₁ -C₈ alkyl, C₂ -C₈ alkynyl, C₃ -C₈ cycloalkyl, andCO(CH₂)_(n) CH₃ ;

aryl is defined as phenyl or naphthyl, which is unsubstituted orsubstituted with one, two or three substituents selected from the groupconsisting of: OH, CO₂ R⁴, Br, Cl, F, I, CF₃, C₁ -C₈ alkoxy, C₁ -C₈alkyl, C₂ -C₈ alkynyl, C₃ -C₈ cycloalkyl, CO(CH₂)_(n) CH₃, or when arylis substituted on adjacent carbons they can form a 5- or 6-memberedfused ring having one, two or three heteroatoms selected from O, N, andS, this ring is unsubstituted or substituted on carbon or nitrogen withone, two or three substituents selected from the group consisting of:OH, CO₂ R⁴, Br, Cl, F, I, CF₃, C₁ -C₈ alkoxy, C₁ -C₈ alkyl, C₂ -C₈alkynyl, C₃ -C₈ cycloalkyl, and CO(CH₂)_(n) CH₃ ;

R² is: OR⁴ or N(R⁵)₂ ;

R³ is:

a) H,

b) C₁ -C₈ alkyl,

c) C₂ -C₈ alkynyl,

d) C₁ -C₈ alkoxyl,

e) C₃ -C₇ cycloalkyl,

f) S(O)_(t) R⁵,

g) Br, Cl, F, I,

h) aryl,

i) heteroaryl,

j) --CHO,

k) --CO--C₁ -C₈ alkyl,

l) --CO-aryl,

m) --CO-heteroaryl,

n) --CO₂ R⁴, or

o) protected aldehyde;

heteroaryl is defined as a 5- or 6-membered aromatic ring containing 1,2 or 3 heteroatoms selected from O, N and S, which is unsubstituted orsubstituted with one, two or three substituents selected from the groupconsisting of: OH, CO₂ R⁴, Br, Cl, F, I, CF₃, C₁ -C₈ alkoxy, C₁ -C₈alkyl, C₂ -C₈ alkynyl, C₃ -C₈ cycloalkyl, and CO(CH₂)_(n) CH₃ ;

n is: 0 to 5;

t is: 0, 1 or 2;

R⁴ is: H, or C₁ -C₈ alkyl;

R⁵ is: H, C₁ -C₈ alkyl, or aryl; and

R⁸, R⁹, R¹⁰ and R¹¹ are independently: H, C₁ -C₈ alkyl, C₂ -C₈ alkynyl,C₁ -C₈ alkoxy, C₁ -C₈ alkylthio, aryl, each of which is unsubstituted orsubstituted with one, two or three substituents selected from the groupconsisting of: OH, CO₂ R⁴, Br, Cl, F, I, CF₃, C₁ -C₈ alkoxy, C₁ -C₈alkyl, C₂ -C₈ alkynyl, C₃ -C₈ cycloalkyl, and CO(CH₂)_(n) CH₃ ;

comprising the following steps:

1) adding to a compound of Formula II in a solvent, ##STR6## a solutionof phosphate buffer to maintain a pH of about 4.0 to about 8.0;

2) maintaining the phosphate-buffered biphasic mixture of the compoundof Formula II at about 0° C. to about 50° C.;

3) adding sodium chlorite and a catalytic amount of TEMPO to themixture; and

4) charging the mixture with a catalytic amount of sodium hypochloriteto oxidize to the compound of Formula I.

DETAILED DESCRIPTION OF THE INVENTION

The present invention discloses a process for preparing a compound ofFormula I: ##STR7## wherein: ##STR8## represents: a) 5- or 6-memberedheterocyclyl containing one, two or three double bonds, but at least onedouble bond and 1, 2 or 3 heteroatoms selected from O, N and S, theheterocyclyl is unsubstituted or substituted with one, two or threesubstituents selected from the group consisting of: OH, CO₂ R⁴, Br, Cl,F, I, CF₃, C₁ -C₈ alkoxy, C₁ -C₈ alkyl, C₂ -C₈ alkynyl, C₃ -C₈cycloalkyl, and CO(CH₂)_(n) CH₃,

b) 5- or 6-membered carbocyclyl containing one or two double bonds, butat least one double bond, the carbocyclyl is unsubstituted orsubstituted with one, two or three substituents selected from the groupconsisting of: OH, CO₂ R⁴, Br, Cl, F, I, CF₃, C₁ -C₈ alkoxy, C₁ -C₈alkyl, C₂ -C₈ alkynyl, C₃ -C₈ cycloalkyl, and CO(CH₂)_(n) CH₃,

c) aryl, wherein aryl is as defined below,

C₁ -C₈ alkoxy, C₁ -C₈ alkyl, C₂ -C₈ alkynyl, C₃ -C₈ cycloalkyl, areunsubstituted or substituted with one, two or three substituentsselected from the group consisting of: OH, CO₂ R⁴, Br, Cl, F, I, CF₃, C₁-C₈ alkoxy, C₁ -C₈ alkyl, C₂ -C₈ alkynyl, C₃ -C₈ cycloalkyl, andCO(CH₂)_(n) CH₃ ;

aryl is defined as phenyl or naphthyl, which is unsubstituted orsubstituted with one, two or three substituents selected from the groupconsisting of: OH, CO₂ R⁴, Br, Cl, F, I, CF₃, C₁ -C₈ alkoxy, C₁ -C₈alkyl, C₂ -C₈ alkynyl, C₃ -C₈ cycloalkyl, CO(CH₂)_(n) CH₃ or when arylis substituted on adjacent carbons they can form a 5- or 6-memberedfused ring having one, two or three heteroatoms selected from O, N, andS, this ring is unsubstituted or substituted on carbon or nitrogen withone, two or three substituents selected from the group consisting of:OH, CO₂ R⁴, Br, Cl, F, I, CF₃, C₁ -C₈ alkoxy, C₁ -C₈ alkyl, C₂ -C₈alkynyl, C₃ -C₈ cycloalkyl, and CO(CH₂)_(n) CH₃ ;

R² is: OR⁴ or N(R⁵)₂ ;

R³ is:

a) H,

b) C₁ -C₈ alkyl,

c) C₂ -C₈ alkynyl,

d) C₁ -C₈ alkoxyl,

e) C₃ -C₇ cycloalkyl,

f) S(O)_(t) R⁵,

g) Br, Cl, F, I,

h) aryl,

i) heteroaryl,

j) --CHO,

k) --CO--C₁ -C₈ alkyl,

l) --CO--aryl,

m) --CO--heteroaryl,

n) --CO₂ R⁴, or

o) protected aldehyde;

heteroaryl is defined as a 5- or 6-membered aromatic ring containing 1,2 or 3 heteroatoms selected from O, N and S, which is unsubstituted orsubstituted with one, two or three substituents selected from the groupconsisting of: OH, CO₂ R⁴, Br, Cl, F, I, CF₃, C₁ -C₈ alkoxy, C₁ -C₈alkyl, C₂ -C₈ alkynyl, C₃ -C₈ cycloalkyl, and CO(CH₂)_(n) CH₃ ;

n is: 0 to 5;

t is: 0, 1 or 2;

R⁴ is: H, or C₁ -C₈ alkyl;

R⁵ is: H, C₁ -C₈ alkyl, or aryl; and

R⁸, R⁹, R¹⁰ and R¹¹ are independently: H, C₁ -C₈ alkyl, C₂ -C₈ alkynyl,C₁ -C₈ alkoxy, C₁ -C₈ alkylthio, aryl, each of which is unsubstituted orsubstituted with one, two or three substituents selected from the groupconsisting of: OH, CO₂ R⁴, Br, Cl, F, I, CF₃, C₁ -C₈ alkoxy, C₁ -C₈alkyl, C₂ -C₈ alkynyl, C₃ -C₈ cycloalkyl, and CO(CH₂)_(n) CH₃ ;

comprising the following steps:

1) adding to a compound of Formula II in a solvent, ##STR9## a solutionof phosphate buffer to maintain a pH of about 4.0 to about 8.0;

2) maintaining the phosphate-buffered biphasic mixture of the compoundof Formula II at about 0° C. to about 50° C.;

3) adding sodium chlorite and a catalytic amount of TEMPO to themixture; and

4) charging the mixture with a catalytic amount of sodium hypochloriteto oxidize to the compound of Formula I.

The process as recited above, wherein the solvent is selected from thegroup consisting of: acetonitrile, tetrahydrofuran, acetone, tertiary C₄-C₈ -alcohol, diethyl ether, DME (dimethyl ether), diglyme, triglyme,MTBE (methyl t-butyl ether), toluene, benzene, hexane, pentane, dioxane,dichloromethane, chloroform, carbon tetrachloride, or a mixture of saidsolvents.

The process as recited above, wherein the phosphate buffer comprises anaqueous mixture of NaOH, KOH, KH₂ PO₄, NaH₂ PO₄, K₂ HPO₄ and Na₂ HPO₄sufficient to maintain a pH of about 4.0 to about 8.0, and preferably apH of about 6.5 to about 7.0.

The process as recited above, wherein TEMPO(2,2,6,6-tetramethyl-1-piperidinyloxy, free radical) is used in about1.0 to about 10.0 mole percent, preferably about 5.0 to about 7.0 molepercent.

The process as recited above, wherein sodium chlorite is used in about1.0 to about 3.0 equivalents, and preferably about 2.0 equivalentsrelative to the compound of Formula II.

The process as recited above, wherein sodium hypochlorite is used inabout 1.0 to about 8.0 mole percent, preferably about 2.0 to about 5.0mole percent.

The process as recited above, wherein the reaction temperature is about0° C. to about 50° C., and preferably about 35° C. to about 40° C.

The process as recited above, wherein the reaction time is up to about24 hours, and preferably between about 2 and about 4 hours.

The process as recited above, wherein the compound of Formula I is##STR10## and the compound of Formula II is ##STR11##

A process for the preparation of a compound of Formula I ##STR12##comprising the following steps: 1) treating a compound of Formula II,##STR13## in an biphasic solution of water and an organic solvent with asolution of HCl to adjust the pH to about 3 to about 4;

2) separating the layers and washing the organic solvent with water;

3) extracting the organic layer with an aqueous solution of NaOH andisolating the basic aqueous layer;

4) adding to the basic aqueous layer, a solvent and a solution ofphosphate buffer to maintain a pH of about 4.0 to about 8.0 in themixture containing the phosphate-buffered biphasic solution;

5) heating the mixture containing the phosphate-buffered solution andthe compound of Formula II in the solvent to about 30° C. to about 40°C.;

6) adding sodium chlorite and a catalytic amount of TEMPO to the heatedmixture;

7) charging the mixture with a catalytic amount of sodium hypochloritefor up to about 4 hours to oxidize to the disodium salt of the compoundof Formula I;

8) quenching the oxidation reaction containing the salt of the compoundof Formula I with a solution of sodium sulfite;

9) washing the quenched aqueous solution containing the salt of thecompound of Formula I with a nonpolar organic solvent;

10) acidifying the washed aqueous solution containing the salt of thecompound of Formula I in an organic solvent with HCl to a pH of about3.0 to about 4.0 to give the compound of Formula I in a nonpolar organicsolvent; and

11) washing the organic solution containing the compound of Formula Iwith water, isolating the organic layer, and evaporating the organicsolvent from the organic layer to give the compound of Formula I.

It is further understood that the substituents recited above wouldinclude the definitions recited below.

The protected aldehyde substitutent recited above denotes those aldehydeprotecting groups outlined by Greene and Wuts in Chapter 4 of"Protective Groups in Organic Synthesis" 2nd Edition, John Wiley & Son,Inc. (1991).

The alkyl substituents recited above denote straight and branched chainhydrocarbons of the length specified such as methyl, ethyl, isopropyl,isobutyl, tert-butyl, neopentyl, isopentyl, etc.

Cycloalkyl denotes rings composed of 3 to 8 methylene groups, each ofwhich may be substituted or unsubstituted with other hydrocarbonsubstituents, and includes for example cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and 4-methylcyclohexyl.

The alkoxy substituent represents an alkyl group as described aboveattached through an oxygen bridge.

The aryl substituent represents phenyl and 1-naphthyl or 2-naphthyl,including aryls substitued with a 5- or 6-membered fused ring, such asan unsubstituted and substituted methylenedioxy, oxazolyl, imidazolyl,or thiazolyl ring.

The heteroaryl substituent represents a carbazolyl, furanyl, thienyl,pyrrolyl, isothiazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl,pyrazolyl, pyrazinyl, pyridyl, pyrimidyl, or purinyl.

The heterocyclyl substituent represents, oxazolidinyl, thiazolidinyl,imidazolidinyl, thiazolidinyl, oxadiazolyl, or thiadiazolyl.

Each of the above substituents (alkyl, alkynyl, alkoxy, aryl,heteroaryl, or heterocyclyl) can be either unsubstituted or substitutedas defined within the description.

The α,β-unsaturated ester or amide ##STR14## can generally be preparedin two steps: 1) a coupling reaction at the one position of Ring A##STR15## wherein R³ is CHO, Z is a leaving group, such as Br, Cl, I,OTriflyl, OTosyl or OMesyl and R² is OR⁴ or N(R⁵)₂ ; and

2) the conversion of the aldehyde (R³ =CHO) to the desired chiralauxiliary (R³), wherein R³ represents ##STR16## X and Y areindependently: O, S, or NR⁵ ; R⁴ is C₁ -C₈ alkyl; R⁵ is: C₁ -C₈ alkyl,or aryl; R^(c), R^(d), R^(e) and R^(f) are independently: H, C₁ -C₈alkyl, and aryl, such that either R^(c) and R^(d) are not the sameand/or R^(e) and R^(f) are not the same, or R^(c) and R^(e) or R^(d) andR^(f) can join to form a 5- or 6-membered ring, which is unsubstitutedor substituted with one, two or three substituents selected from thegroup consisting of: OH, CO₂ R⁴, Br, Cl, F, I, CF₃, C₁ -C₈ alkoxy, C₁-C₈ alky, C₂ -C₈ alkynyl, C₃ -C₈ cycloalkyl, CO(CH₂)_(n) CH₃,CO(CH₂)_(n) CH₂ N(R⁵)₂ ; and n is o to 5.

Commercially available pyridone 1 is alkylated via its dianion withpropyl bromide, and the product is then converted into the bromopyridine3a using a brominating agent such as PBr₃. The nitrile 3a is thenreduced to the aldehyde 3 using diisobutyl aluminum hydride (DIBAL). Thealdehyde then undergoes a Heck reaction with t-butyl acrylate usingNaOAc, (allyl)₂ PdCl₂, tri-o-tolylphosphine, toluene, reflux to providethe unsaturated ester 4a in high yield. The unsaturated ester 4a is thenheated with pseudoephedrine, or alternatively, N-methyl-cis-aminoindanol(not shown in the schemes), and acetic acid in toluene to give theprotected aldehyde 5. ##STR17##

Commercially available acid 10 is reduced with in situ borane (NaBH₄/BF₃ •Et₂ O) to the alcohol 11, which is then converted into thechloride 13, by treatment with SOCl₂ in dimethylformamide (DMF).##STR18##

Commercially available 1,2-aminoindanol 7 is acylated (propionylchoride, K₂ CO₃) to give amide 8, which is then converted into theacetonide 9 (2-methoxypropene, pyridinium p-toluene-sulfonate (PPTS)).Acetonide 9 is then alkylated with the benzylchloride 13, (LiHMDS) togive 14, which is then hydrolyzed (6N HCl, dioxane) to give thecarboxylic acid 15. Reduction (NaBH₄ /BF₃ •Et₂ O) of the acid providesthe alcohol 16 in high yield and optical purity. Protection of thealcohol 16 (TBSCl, imidazole) provides bromide 17, the precursor toorganolithium 17a. ##STR19##

Compound 17a is added to the α,β-unsaturated ester bearing apseudoephedrine 5 (or the N-methyl-cis-aminoindanol chiral auxiliary,not shown) at -78° to -50° C. Work up with acid, THF and water (toremove the auxiliary) affords compound 6 in high yield and goodstereoselectivity. Please note other chiral axillary groups can beutilized in this asymmetric addition. See WO 98/06698, published by theWorld Intellectual Property Organization on Feb. 19, 1998. ##STR20##

Addition of the Grignard reagent (prepared from the aryl bromide andmagnesium) to compound 6 at -78° C. to about -60° C. in THF affordscompound 7 in quantitative yield and good stereoselectivity. ##STR21##

Cyclization of compound 7 by treatment with diethylchlorophosphate andlithium bis(trimethylsilyl)amide (LHMDS) at about -15° C. to about 10°C. give compound 8. Deprotection by treatment with HCl in acetonitrilefollowed by work up and purification by crystallization of itsbenzylamine salt affords the penultimate key intermediate 9. ##STR22##

Salt breaking followed by oxidation of the primary lacohol 9 accordingto the present invention gives the dicarboxylic acid 10 in high yield.##STR23##

The instant invention can be understood further by the followingexamples, which do not constitute a limitation of the invention.

EXAMPLE 1

Preparation of 2-bromo-5-methoxybenzyl alcohol ##STR24##

Sodium borohydride (8.6 g) is slurried in THF (150 mL KF=150 μg/mL) in around bottom flask equipped with a thermocouple, an addition funnel, anitrogen inlet a mechanical stirrer and a cooling bath.2-Bromo-5-methoxybenzoic acid (50 g) is dissolved in THF (100 mL KF=150μg/mL) is added to the sodium borohydride slurry over 45 min whilemaintaining the temperature at 20-25° C. The reaction must be controlledwith intermittent cooling and by careful monitoring of the additionrate. The mixture is aged for 30 min at 20-25° C. Boron trifluorideetherate (36.9 g) is added over a period of 30 min at 30-35° C.

The addition of boron trifluoride etherate produces a delayed exothermand should be added slowly in order to control the reaction temperature.The resulting white slurry is aged for 1 h at 30-35° C. and then sampledfor HPLC assay. A peak at RT=8.7 min is an impurity related to thestarting material. The acid is at RT=9.1 min.

The reaction mixture is cooled to 15° C. and carefully quenched into acold (10° C.) saturated ammonium chloride solution (150 mL) whilemaintaining the temperature <25° C.

Ethyl acetate (500 mL) is added and the layers are separated. Theorganic layer is washed with water (100 mL) and then transfered to a 1 Lround bottom flask equipped for distillation. The solution wasconcentrated and charged with fresh ethyl acetate. This is repeateduntil a solution with a volume of 200 mL has KF<200 μg/mL.The solvent isthen switched to DMF to give the final volume of 200 mL with a KF<200μg/mL.

EXAMPLE 2

Preparation of 2-bromo-5-methoxybenzyl chloride ##STR25##

The DMF solution of the benzyl alcohol (91.3 g in 400 mL KF=300 μg/mL)is charged to a 2 L flask equipped with a mechanical stirrer,thermocouple, N₂ inlet, and cooling bath. The solution is cooled to 0-5°C. and the addition funnel is charged with thionyl chloride (55.0 g).The thionyl chloride is added over a period of 45 min while maintainingthe temperture 5-10° C. The mixture is aged for 1 h at 5° C. and assayedby HPLC.

The addition funnel is charged with water (400 mL) which is addeddropwise to the reaction mixture over a period of 30 min. whilemaintaining the temperture <15° C. The temperature is controlled bycooling and monitoring the rate of addition. The initial addition ofwater is highly exothermic. Using large excess of thionyl chlorideresults in a more exothermic quench. If the quench temperture is notcontrolled, hydrolysis of the benzyl chloride back to the alcohol mayresult.

The resulting thick white slurry is aged for 1 h at 0-5° C. The benzylchloride is isolated by filtration. The cake is washed with (1:1) DMF:H₂O (100 mL) and then water (200 mL). The solid is dried in vacuo to give93 g of the benzyl chloride(94% yield, 96 A %). HPLC assay: Column:Waters Symmetry C8, 4.6×250 mm; UV Detection: 220 nm; Column Temp: 25°C.; Flow rate: 1 mL/min.; Eluent: CH₃ CN:H₂ O:0.1% H₃ PO₄ (70:30); RT(benzyl alcohol)=3.9 min; RT (benzyl chloride)=7.3 min.; and RT(DMF)=2.6 min.

EXAMPLE 3

Preparation of the Acetonide of N-propanoyl (1R,2S)-cis-aminoindano##STR26##

A 5 L 3-neck round bottom flask equipped with a mechanical stirrer, N₂inlet, thermocouple probe, heating mantle, and addition funnel ischarged with (1R,2S)-cis-aminoindanol (100 g), tetrahydrofuran (1.2 L,KF 120 mg/mL), and triethylamine (96 mL, KF 500 μg/mL). The resultingslurry is heated under a N₂ atmosphere to 40-45° C. giving a yellowsolution. Propionyl chloride (59 mL) is charged to an addition funneland added to the solution while maintaining the temperature at 45-50° C.

The temperature is controlled by rate of propionyl chloride addition anda cooling bath. HPLC assay shows >99% amide formed. Methanesulfonic acid(3 mL) is added to the reaction slurry. 2-Methoxypropene (140 mL) ischarged to an addition funnel and added over 30 minutes at a temperatureof 50° C.

The addition of 2-methoxypropene is mildly exothermic. The temperatureis maintained by the rate of addition and a heating mantle. The reactionremains a slurry but does become less thick.

The reaction slurry is aged for 1-2 hours at 50° C. HPLC assay at thispoint shows <0.5 A % of the amide remaining. The amide is not removed inthe isolation so it is important to push the reaction to completion. Thereaction slurry is cooled to 0-5° C. and quenched by addition of 5%aqueous sodium carbonate solution (1 L) and heptane (1 L). The layersare stirred and separated and the organic is washed with water (300 mL).

HPLC assay at this point shows the acetonide in >98 A % and >90% yield.The acetonide/THF/heptane solution is filtered into a 2 L round bottomflask and the solution is distilled to a final volume of 700 mL. Heptane(1 L) is added and the solution is distilled to a final volume of 700mL. The distillation is done under partial vacuum at ˜50° C. NMR assayat this point shows <2 mol % THF. The solution is allowed to cool and isseeded with acetonide at 35-40° C. The thick slurry is aged for 1 hourat ambient temperature then cooled to 0-5° C. and aged for 1 hour. Theslurry is filtered and the cake is washed with cold heptane (200 mL) andair dried to yield acetonide as a crystalline white solid (141.1 g, 85%yield, 99.6 A %).

EXAMPLE 4

Alkylation of the Acetonide with 2-bromo-5-methoxybenzyl chloride.##STR27##

A THF solution (2 L, KF<200 μg/mL) of the acetonide (252 g) and thebenzyl chloride (255 g) is cooled to -10° C. Lithiumbis(trimethylsilyl)amide (1.45 L) is added dropwise over 5 h at 0-2° C.The mixture is then aged for 1.5 h and assayed by HPLC.

The reaction is quenched by adding aqueous saturated ammonium chloridesolution (1 L). The initial addition of the ammonium chloride should beslow in order to control the foaming. The rate can be increased when thefoaming subsides.

The quenched reaction is then transfered into a mixture of aqueousammonium chloride (1.5 L), water (0.5 L), and ethyl acetate (3 L). Themixture is then agitated for 15 min and the layers are separated. Theorganic layer is washed with water (1 L) and brine (0.5 L). The ethylacetate solution is concentrated to a low volume and solvent switched to1,4 dioxane. The dioxane solution is adjusted to a final volume of 1.8L.

The dioxane solution of the coupled product is charged to a 12 L roundbottom flask and 6 M HCl (1.5 L) is charged. The mixture is heated toreflux and monitored by HPLC.

The mixture is cooled to 20° C. and MTBE (3 L) is added. The mixture isagitated for 15 min and the layers are separated. The organic layer iswashed with water (1 L). The MTBE solution of the crude acid isextracted with 0.6 M sodium hydroxidize (2 L). The aqueous solution ofthe sodium salt of the acid is combined with MTBE (2.5 L) and cooled to10° C.

The two phase mixture is acidified with 5.4 M sulfuric acid (250 mL),agitated for 15 min, settled and the layers separated. The MTBE solutionof the acid is washed with water (0.5 L). The MTBE solution of the acidis dried by distilation and then solvent switched to THF. The finalvolume of the THF is 2 L with a KF <250 μg/mL. HPLC assay: column:Waters Symmetry; Eluent: acetontrile: water: phosphoric acid(70:30:0.1); Flow rate: 1 mL/min.; RT (acetonide)=4.5 min.; RT (benzylchloride)=7.5 min.; RT (coupled product)=11.5 min.; RT (aminondanol)=1.7min.; RT (hydroxyamide)=1.7 min.; and RT (acid)=4.5 min.

EXAMPLE 5

Preparation of 3-(2-bromo-5-methoxyphenyl)-2-methylpropanol ##STR28##

Sodium borohydride (33 g) is slurried in THF (0.5 L KF=200 mg/mL) in around bottom flask. The THF solution (2 L) of the acid is added to thesodium borohydride slurry over 1 h while maintaining the temperature at20-25° C.

The reaction is controlled with a cooling bath and by carefullymonitoring the addition rate. A nitrogen sweep and proper venting of thehydrogen is also important.

The mixture is aged for 30 min at 20-25° C. Boron trifluoride etherate(152 g) is added over 1 h at 30-35° C. The addition produces a delayedexotherm and should be carefully monitored in order to control thereaction temperature. The resulting milky white slurry is aged for 1 hat 30° C. and sampled for HPLC assay.

The reaction mixture is cooled to 15° C. and carefully quenched in acold (10° C.) ammonium chloride solution (1.5 L) while maintaining thetemperature at 25° C. The rate of hydrogen evolution is controlled bythe rate of the addition of the mixture into the ammonium chloride. Thequenched mixture is distilled in vacuo to remove the THF. The aqueouslayer is extracted with MTBE (1.5 L) and the organic layer is dried byflushing with additional MTBE. The MTBE solution is then solventswitched to hexanes and adjusted to a volume of 350 mL and seeded. Theslurry is aged for 2 h at 20° C. and then cooled to 0-5° C. aged for 1 hand filtered. The cake is washed with cold hexanes (200 mL). The solidis dried under a nitrogen sweep. The isolated solid (164 g) is >99 A %by HPLC and >99% ee.

HPLC: Column: Waters Symmetry C8; Solvent: acetonitrile:water:phosphoric acid (50:50:0.1); Flow rate: 1 mL/min.; Detection: 220 nm; RT(acid)=10.2 min.; RT (alcohol)=10.7min.

Chiral HPLC: Column: Chiracel OD-H; Hexane:2-propanol (97:3); Flow rate:1 mL/min.; Detection: 220 nm; RT minor isomer=21 min.; and RT majorisomer=23 min.

EXAMPLE 6

Preparation of 3-(2-bromo-5-methoxyphenyl)-2-methylpropylt-butyldimethylsilyl ether ##STR29##

Imidazole (1.6 g, 0.023 mol) is added to a solution of the alcohol (5.0g, 0.019 mol) in DMF (15 mL) at 20° C. The addition of imidazole isendothermic and results in a 4-5° C. drop in temperature. TBSCl (3.0 g,0.020 mol) is dissolved in DMF (5 mL) and is added slowly to the abovesolution while maintaining the temperature 20-25° C. using a coolingbath. The reaction is monitored by HPLC.

MTBE (50 mL) is added to the reaction mixture along with water (50 mL)and the phases are separated. The organic is washed with water (50 mL)and then concentrated to 10 mL total volume and solvent switched intoTHF in preparation for the next step. NMR assay of the organic layerafter the second water wash indicates no residual DMF. This is crucialbecause DMF may be problematic in the next step.

¹ H NMR (CDCl₃) δ: 7.41 (d, J=8.74, 1H), 6.77 (d, J=3.04, 1H), 6.63 (dd,J=8.73, 3.06, 1H), 3.78 (s, 3H), 3.50 (d, J=5.75, 2H), 2.89 (dd,J=13.31, 6.15, 1H), 2.45 (dd, J=13.30, 8.26, 1H), 2.03 (m, 1H), 0.94 (s,9H), 0.92 (d, J=5.01, 3H), 0.07 (s, 6H).

¹³ C NMR (CDCl₃) δ: 159.1, 141.6, 133.2, 117.0, 115.4, 113.2, 67.4,55.4, 39.7, 36.3, 26.0 (3C), 18.4, 16.5, -5.3 (2C).

HPLC assay: column, Zorbax Rx C8 (4.6×250 mm); solvent: acetonitrile:water: phosphoric acid 90:10:0.1; flow rate: 1 mL/min; UV Detection: 220nm; Retention times: RT (alcohol)=3.08 min; RT (DMF)=3.17 min; and RT(product)=7.7 min.

EXAMPLE 7

Pseudoephedrine Acetal Formation of t-butyl3-(6-n-butyl-3-formylpyridyl)-2-prop-2-enoate ##STR30##

To a solution of Heck product 4a (2.907 kg) in toluene (7.049 kg) isadded solid (1S,2S)-(+)-pseudoephedrine (1.74 kg) followed by aceticacid (2.87 ml). The reaction mixture is then heated to reflux. Thetoluene/water azeotrope begins to reflux at a pot temperature of 87° C.Over the course of 40 minutes, the pot temperature increases to 110° C.At this time, approximately 160 ml of water has been collected in theDean-Stark trap.

A HPLC assay of an aliquot indicates that all starting Heck product hasbeen consumed.

The reaction is then cooled to 40° C. and pumped into a 50 L extractorand diluted with MTBE (10.67 kg). The organic layer is washed withsaturated NaHCO₃ (12.10 kg ) and then with water (23.64 kg). The organiclayer is concentrated to a volume <10 L and a KF <120 μg/mL. The MTBE isremoved prior to flushing with toluene. Typically 8-10 L of toluene isrequired as flush to obtain the desired KF. The dry toluene solution wasstored under nitrogen until needed.

HPLC Assay: Column: Zorbax Rx-C8 4.6×250 mm; Solvent: Acetonitrile:water95:5; Flow: 1.0 mL/min; UV Detection: 220 nm; RT (toluene)=3.2 min.; RT(Heck Product)=3.9 min.; and RT (N,O, acetal)=5.3 min.

EXAMPLE 8

Conjugate Addition-Hydrolysis ##STR31##

To a solution of arylbromide (4.08 kg) in THF (7.34 kg, KF<150 μg/mL) at-82° C. is added a 2.25 M solution of n-BuLi in hexanes (4.87 L). Theaddition takes 2 h and the internal temperature is maintained below -72°C.

Assay by HPLC indicates that the lithiation is complete after additionof the n-BuLi. The lithiation reaction is instantaneous at the reactiontemperature. The purpose of checking an aliquot is to insure that theproper amount of n-BuLi is charged. To the above solution (re-cooled toapproximately -80° C.) is added the pre-cooled (approximately -65° C.)toluene solution (KF<150 μg/mL) of the enoate. The addition is done veryrapidly with the aid of a pump (addition time <5min.) and the reactiontypically exotherms to -32° C.

In order to insure efficient pumping, the enoate solution was dilutedwith an additional 3-4 L of toluene.

The reaction is re-cooled to -60° C. and quenched carefully with 2.9 Lof acetic acid. (Warning: exothermic reaction.) The reaction exothermsto approximately -20° C. The quenched reaction mixture is then pumpedinto a 100 L extractor. A citric acid solution (4.82 kg of citric acidin 8 kg of water) is then added and the two-phase mixture is rapidlystirred for 16 h at room temperature. HPLC assay indicates that the N, Oacetal hydrolysis is complete.

The phases are cut and the aqueous layer is extracted with MTBE (14.23kg). The combined organic layers are washed twice with 5% NaHCO₃ (2×23kg). The organic layer is then washed with water (20.55 kg). The pH ofthe water wash should be neutral to slightly basic. The organic layer isdried under reduced pressure to a volume <7 L and a KF<100 μg/mL. TheMTBE is removed prior to flushing with toluene. Approximately 30 kg oftoluene is needed as flush to obtain the desired KF value. The drytoluene solution is then pumped into a plastic carboy. The 100 Lextractor and pump are then flushed with 2.5 kg of THF. HPLC assayindicates a yield of 4.2 kg (72% from the Heck Product, 3 steps). The eeof the product is determined to be 92%.

HPLC Assay: Column: Zorbax Rx-C8 4.6×250 mm; Solvent: acetonitrile:water95:5; flow rate: 1.0 mL/min.; UV Detection: 220 nm; RT (toluene)=3.2min.; RT (ArH)=5.5 min.; RT (ArBr)=6.5 min.; RT (ArBu )=8.2 min.; RT(Aldehyde Product)=9.5 min.; and RT (N,O acetal Product)=18.2 min.

Chiral HPLC Assav: Column: Whelk-O; Solvent: 97:3Hexane/IPA; flowrate=1.0 mL/min.; RT(toluene)=3.1 min.; RT(minor)=6.8 min.; andRT(major)=7.5min.

EXAMPLE 9

Grignard Addition ##STR32##

Step A: Preparation of the Grignard Reagent

To a 22 L reaction flask equipped with an efficient condenser is chargedMg (240 g, 9.87 mol) and dry THF (8.2 L, KF<100 μg/mL). The mixture isheated to 50° C. after degassing by two vacuum/N₂ cycles. The arylbromide (1.89 kg, 9.40 mol) is then added carefully!

Due to the induction period and very exothermic reaction, the ArBrshould be added very carefully! No more than 10% of the ArBr should beadded before the reaction is initiated as indicated by the exotherm (thebatch temperature will be higher than that of the bath) and color changefrom colorless to pale yellow. Cooling maybe required to control thereaction temperature. Once the reaction is initiated, the heating isstopped and the remaining ArBr is added slowly maintaining a gentlereflux. The reaction mixture is then aged at 50° C. for 2 hours to givea solution of ArMgBr (˜9.4 L, 1.0 M). The reaction is monitored by HPLC.Zorbax SB-C8 4.6×250 mm, 30° C.; 1.50 mL/min; linear gradient: MeCN40-70% in 15 min, 0.1% H₃ PO₄ ; 220 nm; Retention time (min.): ArBr,6.2; ArH, 9.2 min.

Step B: Addition of the Grignard Reagent to the Aldehyde

A dry solution of the crude Michael addition product (4.22 kg in ˜4.7 Ltoluene and 2.5 L THF, KF<200 μg/mL) is charged into a 72 L flask. DryTHF (20 L, KF<100 μg/mL) is added and the mixture is degassed by avacuum/N₂ cycle. After the batch is cooled to -75° C. with a dryice-methanol bath, the ArMgBr prepared above is added slowly maintainingthe batch below -65° C. The mixture is aged at -70° C. for 1 hour andthe completion of the reaction is confirmed by HPLC (<1 A % aldehyde).The reaction mixture is aged for two more hours then pumped into aqueousNH₄ Cl (14 L 20 w %) to quench the reaction. Toluene (14 L) is added andthe mixture is warmed to 20° C. The organic layer is separated andwashed with brine (14 L) to give a solution of the crude Grignardaddition product (50.11 Kg).

Assay by HPLC indicates the presence of 4.67 Kg (91% yield) of theproduct in solution. It is dried with ˜2 kg of anhydrous Na₂ SO₄overnight to remove the bulk of the water then filtered and concentratedto 15 L under vacuum. The KF of the residue should be below 150 μg/mL(flush with additional toluene as needed). It is used directly for thecyclization.

HPLC conditions: Column: Zorbax SB-C8 4.6×250 mm; temperature: 30° C.;Solvent: CH₃ CN: H₂ O:0.1H₃ PO₄ 80:20:0.1 gradient to 100:0:0.1 over 15min.; Flowrate: 1.5 mL/min.; RT (aldehyde)=12.15 min.; RT (majorstereoisomer)=9.93 min.; RT (minor stereoisomer)=10.65 min.

EXAMPLE 10

Cyclization-Deprotection ##STR33##

The Grignard addition product in toluene (˜15 L, KF=130 μg/ml) is cooledto -15° C. and the diethylchorophosphate (1.65 kg, 9.6 mol, 1.45 eq) isadded. Then LiN(TMS)₂ in THF (1.0 M, 28.75 L, 4.35 eq) is added whilekeeping the temperature <5° C. The slurry is aged at 0-10° C. for 4 hrs.More diethyl chlorophosphate and LiN(TMS)₂ may be added as required tocomplete the reaction. The reaction is monitored by HPLC. After 3 h thereaction is typically complete. After the reaction is completed (SM<1%),water (17 L) and acetic acid (4.5 kg, exothermic!) is added whilekeeping the reaction temperature <30° C.

The temperature is controlled by controlling the rate of addition and byusing a cooling bath. After the two layers are separated, the organiclayer is washed with 14 L brine. The organic layer is concentrated undervacuum to minimum volume of 10-12 L and mixed with 20 L acetonitrile andthen cooled to 0° C. Concentrated HCl (13.2 kg) is added slowly whilekeeping the reaction temperature <25° C. The mixture is aged at 20-25°C. overnight.

The product is a mixture of the acid alcohol and the lactone. HPLC (samecolumn and eluents) Time 0 A/B 50/50, 10 min A/B 90/10, 15 min 90/10.Retention time t-butyl ester alcohol 6.4 min, lactone 4.7 min, acidalcohol 2.9 min.

When the t-butyl ester alcohol is consumed (19 hrs), the reactionmixture is cooled to 0° C. and 40% w/w NaOH (˜12.4 kg until pH=3-5) isadded while keeping the temperature <25° C. Water (6 L) is also added.When the pH of the aqueous layer reaches 3, the two layers areseparated. The top organic layer is then mixed with 3.3 kg 40% NaOH (5eq) and 12 L water. The mixture is vigorously stirred for 3 hrs untilall the lactone is consumed (organic layer sample). The two layers arethen separated and to the organic layer is added 20 L MTBE and 20 Lwater and 200 g 40% NaOH. The two layers are separated again aftermixing. The organic layer is mixed with 100 g 40% NaOH, 10 L water and20 L heptane. The layers are separated and the organic layer discarded.

To the combined aqueous layer is added H₃ PO₄ (85%, 4.6 kg, 6 eq) untilpH=3-4 (exothermic, keep the temperature <25° C.) and MTBE (12 L). Afterthe two layers are separated, the aqueous layer is extracted with 20 Ltoluene. The combined organic layer is dried with 1.5 kg Na₂ SO₄ andthen concentrated under vacuum to a volume of ˜10 L. It was flushed with5 L toluene to reach KF=450 μg/ml. The residue is then mixed with 50 LMTBE. Benzylamine (0.85 kg, 1.2 eq) is added as a solution in 3 L MTBE.Only 1.5 L of this solution is added initially and the batch is seededwith 0.5 g of the benzylamine salt. The batch is aged for one hour forthe salt to precipitate. The rest of the benzylamine solution is addedover 30 min. Additional 7 L MTBE is used for rinse. The batch is aged atambient temperature overnight. The solid is collected by filtration andwashed with 3×4 L MTBE until the wash is nearly colorless. The batch isdried with nitrogen flow and suction, wt. 2.96 kg (72% yield). HPLCshowed ˜95 wt % pure and 98.5 area %. HPLC: Column: Zorbax SB C-8 column4.6×250 mm size; Solvent: Eluent: A: MeCN and B: 0.1% H₃ PO₄ ; Gradient:Time 0 A/B 80/20, 10 min 95/5; 20 min A/B 98/2; 25 min 98/2; Flow rate:1.5 ml/min; UV detection: 220 nm; RT (Grignard product)=10.9 min.; RT(intermediate)=11.7 min.; RT (intermediate)=13.2 min.; RT (product)=12.2min

EXAMPLE 11

Oxidation of Primary Alcohol-TEMPO Oxidation ##STR34##

A mixture of the benzylamine salt of the hydroxy acid (25.0 g, 40.0mmol) in MTBE (300 mL) and water (100 mL) is treated with 2.0 N HCl (˜20mL) until pH=3-4. The organic layer is washed with water (2×100 mL) thenextracted with NaOH (140 mL 0.63 N NaOH). To the NaOH extract are addedMeCN (200 mL) and NaH₂ PO₄ (13.80 g, 100 mmol) and the mixture is heatedto 35° C. The pH of the mixture should be 6.7. TEMPO (436 mg, 2.8 mmol)is added followed by a simultaneous addition (over 2 h) of a solution ofsodium chlorite (9.14 g 80%, 80.0 mmol in 40 mL water) and dilute bleach(1.06 mL 5.25% bleach diluted into 20 mL, 2.0 mol %).

The sodium chlorite solution and bleach should not be mixed prior to theaddition since the mixture appears to be unstable. The addition shouldbe carried out as follows: approximately 20% of the sodium chloritesolution is added followed by 20% of the dilute bleach. Then the rest ofthe NaClO₂ solution and dilute bleach are added simultaneously over 2 h.

The mixture is aged at 35° C. until the reaction is complete (<2 A % SM,2-4 h). The batch is cooled to rt, water (300 mL) is added and the pH isadjusted to 8.0 with 2.0 N NaOH (˜48 mL). The reaction is quenched bypouring into cold (0° C.) Na₂ SO₃ solution (12.2 g in 200 mL water)maintained <20° C.

The pH of the aqueous layer should be 8.5-9.0. After aging for 0.5 hourat room temperature, MTBE (200 mL) is added with stirring. The organiclayer is discarded and aqueous layer is acidified with 2.0 N HCl (˜100mL) to pH=3-4 after more MTBE (300 mL) is added. The organic layer iswashed with water (2×100 mL), brine (150 mL) to give a solution of thecrude dicarboxylic acid in 90-95% yield (19.1-20.2 g). HPLC conditions:Column: YMC-ODS AM 4.6×250 mm; Flow rate: 1.00 mL/min; Solvent: MeCN50-80% in 15 min, 0.1% H₃ PO₄ ; Temperature: 30° C.; UV detection: 220nm; RT (hydroxy acid)=5.8 min.; RT (dicarboxylic acid)=7.8 min.

What is claimed is:
 1. A process for preparing a compound of Formula I:##STR35## wherein: ##STR36## represents: a) 5- or 6-memberedheterocyclyl containing one, two or three double bonds, but at least onedouble bond and 1, 2 or 3 heteroatoms selected from O, N and S, theheterocyclyl is unsubstituted or substituted with one, two or threesubstituents selected from the group consisting of: OH, CO₂ R⁴, Br, Cl,F, I, CF₃, C₁ -C₈ alkoxy, C₁ -C₈ alkyl, C₂ -C₈ alkynyl, C₃ -C₈cycloalkyl, and CO(CH₂)_(n) CH₃,b) 5- or 6-membered carbocyclylcontaining one or two double bonds, but at least one double bond, thecarbocyclyl is unsubstituted or substituted with one, two or threesubstituents selected from the group consisting of: OH, CO₂ R⁴, Br, Cl,F, I, CF₃, C₁ -C₈ alkoxy, C₁ -C₈ alkyl, C₂ -C₈ alkynyl, C₃ -C₈cycloalkyl, and CO(CH₂)_(n) CH₃, c) aryl, wherein aryl is as definedbelow,C₁ -C₈ alkoxy, C₁ -C₈ alkyl, C₂ -C₈ alkynyl, C₃ -C₈ cycloalkyl,are unsubstituted or substituted with one, two or three substituentsselected from the group consisting of: OH, CO₂ R⁴, Br, Cl, F, I, CF₃, C₁-C₈ alkoxy, C₁ -C₈ alkyl, C₂ -C₈ alkynyl, C₃ -C₈ cycloalkyl, andCO(CH₂)_(n) CH₃ ; aryl is defined as phenyl or naphthyl, which isunsubstituted or substituted with one, two or three substituentsselected from the group consisting of: OH, CO₂ R⁴, Br, Cl, F, I, CF₃, C₁-C₈ alkoxy, C₁ -C₈ alkyl, C₂ -C₈ alkynyl, C₃ -C₈ cycloalkyl, CO(CH₂)_(n)CH₃ or when aryl is substituted on adjacent carbons they can form a 5-or 6-membered fused ring having one, two or three heteroatoms selectedfrom O, N, and S, this ring is unsubstituted or substituted on carbon ornitrogen with one, two or three substituents selected from the groupconsisting of: OH, CO₂ R⁴, Br, Cl, F, I, CF₃, C₁ -C₈ alkoxy, C₁ -C₈alkyl, C₂ -C₈ alkynyl, C₃ -C₈ cycloalkyl, and CO(CH₂)_(n) CH₃ ; R² is:OR⁴ or N(R⁵)₂ ; R³ is:a) H, b) C₁ -C₈ alkyl, c) C₂ -C₈ alkynyl, d) C₁-C₈ alkoxyl, e) C₃ -C₇ cycloalkyl, f) S(O)_(t) R⁵, g) Br, Cl, F, I, h)aryl, i) heteroaryl, j) --CHO, k) --CO--C₁ -C₈ alkyl, l) --CO--aryl, m)--CO--heteroaryl, n) --CO₂ R⁴, or o) protected aldehyde; heteroaryl isdefined as a 5- or 6-membered aromatic ring containing 1, 2 or 3heteroatoms selected from O, N and S, which is unsubstituted orsubstituted with one, two or three substituents selected from the groupconsisting of: OH, CO₂ R⁴, Br, Cl, F, I, CF₃, C₁ -C₈ alkoxy, C₁ -C₈alkyl, C₂ -C₈ alkynyl, C₃ -C₈ cycloalkyl, and CO(CH₂)_(n) CH₃ ; n is: 0to 5; t is: 0, 1 or 2; R⁴ is: H, or C₁ -C₈ alkyl; R⁵ is: H, C₁ -C₈alkyl, or aryl; R⁸, R⁹, R¹⁰ and R¹¹ are independently: H, C₁ -C₈ alkyl,C₂ -C₈ alkynyl, C₁ -C₈ alkoxy, C₁ -C₈ alkylthio, aryl, each of which isunsubstituted or substituted with one, two or three substituentsselected from the group consisting of: OH, CO₂ R⁴, Br, Cl, F, I, CF₃, C₁-C₈ alkoxy, C₁ -C₈ alkyl, C₂ -C₈ alkynyl, C₃ -C₈ cycloalkyl, andCO(CH₂)_(n) CH₃ ; comprising the following steps:1) adding to a compoundof Formula II in a solvent, ##STR37## a solution of phosphate buffer tomaintain a pH of about 4.0 to about 8.0; 2) maintaining thephosphate-buffered biphasic mixture of the compound of Formula II atabout 0° C. to about 50° C.; 3) adding sodium chlorite and a catalyticamount of TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy, free radical) tothe mixture; and 4) charging the mixture with a catalytic amount ofsodium hypochlorite to oxidize to the compound of Formula I.
 2. Theprocess as recited in claim 1, wherein the solvent is selected from thegroup consisting of: acetonitrile, tetrahydrofuran, acetone, tertiary C₄-C₈ -alcohol, diethyl ether, DME (dimethyl ether), diglyme, triglyme,MTBE (methyl t-butyl ether), toluene, benzene, hexane, pentane, dioxane,dichloromethane, chloroform, carbon tetrachloride, or a mixture of saidsolvents.
 3. The process as recited in claim 2, wherein the phosphatebuffer comprises an aqueous mixture of NaOH, KOH, KH₂ PO₄, NaH₂ PO₄, K₂HPO₄ and Na₂ HPO₄ sufficient to maintain a pH of about 4.0 to about 8.0.4. The process as recited in claim 3, wherein TEMPO(2,2,6,6-tetramethyl-1-piperidinyloxy, free radical) is used in about1.0 to about 10.0 mole percent.
 5. The process as recited in claim 4,wherein sodium chlorite is used in about 1.0 to about 3.0 equivalents.6. The process as recited in claim 5, wherein sodium hypochlorite isused in about 1.0 to about 8.0 mole percent.
 7. The process as recitedin claim 6, wherein the reaction temperature is about 0° C. to about 50°C.
 8. The process as recited in claim 7, wherein the phosphate buffercomprises an aqueous mixture of NaOH, KOH, KH₂ PO₄, NaH₂ PO₄, K₂ HPO₄and Na₂ HPO₄ sufficient to maintain a pH of about 6.5 to about 7.0. 9.The process as recited claim 8, wherein TEMPO(2,2,6,6-tetramethyl-1-piperidinyloxy, free radical) is used in about5.0 to about 7.0 mole percent.
 10. The process as recited in claim 9,wherein sodium chlorite is used in about 2.0 equivalents relative to thecompound of Formula II.
 11. The process as recited in claim 10, whereinsodium hypochlorite is used in about 2.0 to about 5.0 mole percent. 12.The process as recited in claim 11, wherein the reaction temperature isabout 35° C. to about 40° C.
 13. The process as recited in claim 12,wherein the compound of Formula II is ##STR38##
 14. The process asrecited in claim 13, wherein the solvent is acetonitrile.
 15. A processfor the preparation of a compound of Formula I comprising the followingsteps:1) treating a compound of Formula II, ##STR39## in an biphasicsolution of water and an organic solvent with a solution of HCl toadjust the pH to about 3 to about 4; 2) separating the layers andwashing the organic solvent with water; 3) extracting the organic layerwith an aqueous solution of NaOH and isolating the basic aqueous layer;4) adding to the basic aqueous layer, a solvent and a solution ofphosphate buffer to maintain a pH of about 4.0 to about 8.0 in themixture containing the phosphate-buffered solution; 5) heating themixture containing the phosphate-buffered solution and the compound ofFormula II in the solvent to about 30° C. to about 40° C.; 6) addingsodium chlorite and a catalytic amount of TEMPO(2,2,6,6-tetramethyl-1-piperidinyloxy, free radical) to the heatedmixture; 7) charging the mixture with a catalytic amount of sodiumhypochlorite for up to about 4 hours to oxidize to the disodium salt ofthe compound of Formula I; 8) quenching the oxidation reactioncontaining the salt of the compound of Formula I with a solution ofsodium sulfite; 9) washing the quenched aqueous solution containing thesalt of the compound of Formula I with a nonpolar organic solvent; 10)acidifying the washed aqueous solution containing the salt of thecompound of Formula I in an organic solvent with HCl to a pH of about3.0 to about 4.0 to give the compound of Formula I in a nonpolar organicsolvent; and 11) washing the organic solution containing the compound ofFormula I with water, isolating the organic layer, and evaporating theorganic solvent from the organic layer to give the compound of FormulaI.